Abstract
BackgroundAcute graft-versus-host disease (aGVHD) remains a major obstacle against favorable clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). T helper cells including Th17 play key roles in aGVHD pathogenesis. Donor regulatory T cell (Tregs) adoptive therapy reduces aGVHD without weakening graft-versus-leukemia effect (GVL) in both mouse and human, although the purification and ex vivo expansion of Tregs in clinical scenarios remain costly and technically demanding. Hypoxia-inducible factor 1 alpha (HIF-1α) is a key molecule switch that attenuates Treg but promotes Th17 development. However, whether pharmacological inhibition of HIF-1α reduces aGVHD via increasing Treg development and diminishing Th17 responses remains unexplored.MethodsBy using alloantigen-specific mixed lymphocyte culture and murine models of aGVHD and GVL, we evaluated the impacts of HIF-1α inhibition by echinomycin on the alloantigen-specific CD4 T cell responses ex vivo, as well as on aGVHD and GVL effect following allo-HSCT.ResultsEx vivo echinomycin treatment resulted in increased number of Tregs in the culture as well as reduced alloantigen-specific Th17 and Th1 responses. In vivo echinomycin treatment reduced GVHD scores and prolonged survival of mice following allo-HSCT, which is associated with increased number of donor Tregs and reduced number of Th17 and Th1 in lymphoid tissues. In murine model of leukemia, echinomycin treatment preserved GVL effect and prolonged leukemia free survival following allo-HSCT.ConclusionsEchinomycin treatment reduces aGVHD and preserves GVL effect via increasing donor Treg development and diminishing alloantigen-specific Th17 and Th1 responses following allo-HSCT, presumably via direct inhibition of HIF-1α that results in preferential Treg differentiation during alloantigen-specific CD4 T cell responses. These findings highlight pharmacological inhibition of HIF-1α as a promising strategy in GVHD prophylaxis.
Highlights
Acute graft-versus-host disease remains a major obstacle against favorable clinical outcomes following allogeneic hematopoietic stem cell transplantation
HIF‐1α inhibitor echinomycin increases regulatory T cells (Treg) development and diminishes alloantigen‐specific T helper cell responses ex vivo To determine the impact of hypoxia-inducible factor 1 alpha (HIF-1α) inhibition on alloantigen-specific CD4 T cell responses, we cultured bone marrow derived dendritic cells (BMDCs) of Balb/c mice with allogeneic splenic CD4 T cells purified from C57BL/6 mice, in the presence of the HIF-1α inhibitor echinomycin
There was no increase in numbers of CD4 T cell subsets on day 3 or day 6 of culture when CD4 T cells were cocultured with syngeneic BMDCs
Summary
Acute graft-versus-host disease (aGVHD) remains a major obstacle against favorable clinical outcomes following allogeneic hematopoietic stem cell transplantation (allo-HSCT). Accumulating data have shown that such a pan-T cell targeting regimen results in weakened GVL effect as evidenced by the increased risk of graft failure, delayed immune reconstitution, and leukemia relapse [9,10,11] For these reasons, improved prophylactic and/ or therapeutic strategies are in urgent need to separate aGVHD and GVL. Clinical studies revealed that higher number of Tregs in HSC graft are associated with reduced GVHD, and abundance of Foxp gene expression was significantly higher in non-GVHD than GVHD patients following allo-HSCT [15, 16] These studies provided compelling evidence that prevention of GVHD without weakening GVL can be achieved via increasing the number of donor Tregs in HSC recipients. These obstacles remain challenges to the wide application of Treg infusion as a GVHD prophylactic regimen in clinical scenarios
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